Why does height depend on genes and hormones?
Somatic growth, the increase in body size, is the first phase of puberty. Many things influence it: genetic, nutritional, environmental and hormonal factors. Genetic and hormonal determinants have particular physiological importance.
The picture starts at the growth plate, the layer of cartilage at the ends of the long bones where new bone is laid down. Adult height is determined largely by genes acting on this plate, because the plate is where the long bones add length. Height then has two parts. Genes set how much growth is possible at all, a ceiling. Hormones decide when and how fast that growth happens, a clock.
How do the sex chromosomes show the effect of genes?
If genes set the ceiling, the number of sex chromosomes a person carries should show it, and it does. More than 50 loci are linked to height determination, so height is not the work of one gene. The sex chromosomes are especially informative because they carry the same height-determining genes in different numbers of copies, so copy number can be compared with stature.
Ordered from tallest to shortest, stature runs XYY > XY > XXX > XX > X. Two observations sit in this ranking. Every extra sex chromosome adds height. But there is an exception: XY is taller than XXX, although XY carries one copy of the gene fewer.
How does one gene, SHOX, explain the ranking?
Both observations follow from a single gene, SHOX (short stature homeobox). It lies in the pseudoautosomal region (PAR), a short stretch present on both the X and the Y chromosome. SHOX encodes a transcription factor and is expressed in the chondrocytes of the growth plate, which produce new bone. The dose of working SHOX protein sets how much long-bone growth the plate can sustain. SHOX is likely to regulate how these cells develop, and it appears to regulate their death.
Two features of the PAR explain the ranking.
- SHOX escapes X-chromosome inactivation. In females one of the two X chromosomes is largely silenced in each cell, but the PAR escapes that silencing, so SHOX is expressed from both X chromosomes. Each extra sex chromosome therefore adds SHOX dose, and with it height.
- The SHOX copy on the Y chromosome is expressed more potently than the copy on the X chromosome. This explains why XY, with one copy fewer than XXX, is taller than XXX, which has three X copies and no Y.
The reverse also holds: a lower dose of working SHOX shortens the long bones. Loss of a single SHOX copy accounts for most of the short stature of Turner syndrome. When it occurs without the other Turner features, the loss of a single SHOX copy produces disproportionate short stature of its own, meaning the long bones are affected more than the trunk.
Which hormones set the clock?
Genes only set the ceiling. The clock is hormonal, and the hormones that matter in puberty and somatic growth are growth hormone, thyroid hormones and sex steroids. Growth hormone and thyroid hormones support growth throughout childhood. The pubertal growth spurt is driven mainly by sex steroids. One proposed route is that estrogen acts at the pituitary to activate the growth hormone and IGF-1 axis, so that growth hormone rises during the spurt.
Why do sex steroids both speed growth and end it?
Sex steroids act on the growth plate in two opposite directions at once. They initiate the pubertal growth spurt, and they also advance maturation of the growth plate toward closure. Both effects travel together. A plate that has fused can no longer lengthen the bone, so the same hormones that speed growth also set its end point.
It follows that the timing and amount of sex-steroid exposure decide how much linear growth is banked before the epiphyses fuse.
What happens when sex steroids come too early or never come?
The consequences are clearest when sex-steroid exposure is itself abnormal.
Too early: in congenital adrenal hyperplasia (CAH) the adrenal glands produce excess androgens, a premature increase in sex steroids that brings both effects early. Growth accelerates sooner, but the growth plates also fuse sooner. The result is a child who is “taller than other children, but shorter than other adults.”
Too late or absent: a congenital lack of sex steroids leaves the growth plates open. Linear growth of the long bones continues, so the arms and legs end up disproportionately long compared with the trunk. This is the eunuchoid stature.
Is it estrogen or testosterone that does this?
It was once believed that stature growth and bone development in puberty depend on estrogen in females and testosterone in males. This has been shown not to be true. Males with a mutation of the estrogen receptor, or of aromatase do not have normal bone growth.
Estrogen is the main determinant of both the pubertal growth spurt and the closure of the growth plates in both sexes, so the two-effect picture applies to girls and boys alike. Most of testosterone’s effect on the skeleton is exerted after its conversion to estrogen.
The growth spurt is only the first event of puberty. What appears next, and in what order do breast development, pubic hair and menstruation follow? That is the question of Normal Physiology of Puberty in Girls.